But conventional oral dosage forms offer no control over drug delivery, leading to fluctuations in plasma drug level. These have a disadvantage of a release all or nothing emptying process while the multiple unit particulate system pass through the GIT to avoid the vagaries of gastric emptying and thus release the drug more uniformly. Various approaches have been worked out to improve the retention of oral dosage form in the stomach, e.g. floating systems, swelling and expanding systems, bioadhesive systems, high density systems.
One such approach is Floating Microspheres (Hollow Microspheres). Floating microspheres are gastro-retentive drug delivery systems based on non-effervescent approach. Hollow microspheres are in strict sense, spherical empty particles without core. These microspheres are characteristically free flowing powders consisting of proteins or synthetic polymers, ideally having a size less than 200 micrometer. Gastro-retentive floating microspheres are low-density systems that have sufficient buoyancy to float over gastric contents and remain in stomach for prolonged period. The drug is released slowly at desired rate resulting in increased gastric retention with reduced fluctuations in plasma drug concentration. Floating microspheres to improve patient compliance by decreasing dosing frequency, better therapeutic effect of short half-life drugs can be achieved. Enhanced absorption of drugs which solubilise only in stomach, Gastric retention time is increased because of buoyancy. Floating microspheres are prepared by solvent diffusion and evaporation methods to create the hollow inner core. Floating microspheres are characterized by their micromeritic properties such as particle size, tapped density, compressibility index, true density and flow properties including angle of repose, scanning electron microscopy, in vitro floatability studies, in vivo floatability studies in dogs, in vitro drug release studies and stability studies etc.
Gastric emptying of dosage form is extremely variable process and ability to prolong and control the emptying time is valuable asset for dosage forms, which reside in the stomach for a long period of time than conventional dosage forms. Several difficulties are faced in designing controlled released systems for better absorption and enhanced the bioavailability1. Conventional oral dosage forms such as tablets, capsules provide specific drug concentration in systemic circulation without offering any control over drug delivery and also cause great fluctuations in plasma drug levels. Although single unit floating dosage forms have been extensively studied, these single unit dosage forms have the disadvantage of a release all or nothing emptying process while the multiple unit particulate system pass through the GIT to avoid the vagaries of gastric emptying and thus release the drug more uniformly. The uniform distribution of these multiple unit dosage forms along the GIT could result in more reproducible drug absorption and reduced risk of local irritation; this gave birth to oral controlled drug delivery and led to development of Gastro-retentive floating microspheres2, 3.
Three decades, various attempts have been done to retain the dosage form in the stomach as a way of increasing retention time:
The term bioadhesion describe materials that bind to the biological substrates, such as mucosal memberes. Adhesion of bioadhesive drug delivery devices to the mucosal tissue offeres the possibility of creating an intimate and prolonged contact at the site of administration.This prolonged residence time can result in the enhanced absorption and in combination with a controlled release of drug also improved patient compliance by reducing the frequency of administration. The epithelial adhesive properties of mucin have been applied in the development of gastro retentive drug delivery systems 4, 8.
Floating systems are low-density systems that have sufficient buoyancy to float over the gastric contents and remain in the stomach for a prolonged period. While the system floats over the gastric contents, the drug is released slowly at the desired rate, which results in increased gastro-retention time and reduces fluctuation in plasma drug concentration9-11.
These are capable of swelling to a size that prevents their passage through the pylorus; as a result, the dosage form is retained in the stomach for a longer period of time. Upon coming in contact with gastric fluid, the polymer imbibes water and swells12-14.
Floating drug delivery systems (FDDS) have a bulk density less than gastric fluids and so remain buoyant in the stomach without affecting the gastric emptying rate for a prolonged period of time. While the system is floating on the gastric contents. The drug is released slowly at the desired rate from the system. After release of drug, the residual system is emptied from the stomach. This results in an increased GRT and a better control of the fluctuations in plasma drug concentration. However, besides a minimal gastric content needed to allow the proper achievement of the buoyancy retention principle, a minimal level of floating force (F) is also required to keep the dosage form reliably buoyant on the surface of the meal. To measure the floating force kinetics, a novel apparatus for determination of resultant weight (RW). The RW apparatus operates by measuring continuously the force equivalent to F (as a function of time) that is required to maintain the submerged object. The object floats better if RW is on the higher positive side. This apparatus helps in optimizing FDDS with respect to stability and durability of floating forces produced in order to prevent the drawbacks of unforeseeable intragastric buoyancy capability variations15.
RW or F = F buoyancy - F gravity = (Df - Ds) gV,
Where, RW is total vertical force, Df is fluid density, Ds is object density, V is volume, g is acceleration due to gravity.
FDDS can be divided into two systems:
1. Effervescent systems
2. Non-effervescent systems
The GRT of a drug delivery system can be sustained by incorporating an inflatable chamber, which contains a liquid e.g. ether, cyclopentane, that gasifies at body temperature to cause the inflatation of the chamber in the stomach. The device may also consist of a bioerodible plug made up of PVA, Polyethylene, etc. that gradually dissolves causing the inflatable chamber to release gas and collapse after a predetermined time to permit the spontaneous ejection of the inflatable systems from the stomach16.
These buoyant delivery systems utilize effervescent reactions between carbonate/bicarbonate salts and citric/tartaric acid to liberate CO2, which gets entrapped in the gellified hydrocolloid layer of the systems thus decreasing its specific gravity and making it to float over chyme17, 18.
These buoyant systems utilize matrices prepared with swellable polymers like methocel, polysaccharides like chitosan, effervescent components like sodium bicarbonate, citric acid and tartaric acid or chambers containing a liquid that gasifies at body temperature. The optimal stoichiometric ratio of citric acid and sodium bicarbonate for gas generation is reported to be 0.76:1. The common approach for preparing these systems involves resin beads loaded with bicarbonate and coated with ethylcellulose. The coating, which is insoluble but permeable, allows permeation of water. Thus, carbon dioxide is released, causing the beads to float in the stomach .Other approaches and materials that have been reported are highly swellable hydrocolloids and light mineral oils, a mixture of sodium alginate and sodium bicarbonate, multiple unit floating pills that generate carbon dioxide when ingested, floating minicapsules with a core of sodium bicarbonate, lactose and polyvinyl pyrrolidone coated with hydroxypropyl methylcellulose (HPMC), and floating systems based on ion exchange resin technology, etc.
This type of system, after swallowing, swells unrestrained via imbibition of gastric fluid to an extent that it prevents their exit from the stomach. These systems may be referred to as the ‘plug-type systems’ since they have a tendency to remain lodged near the pyloric sphincter. One of the formulation methods of such dosage forms involves the mixing of drug with a gel, which swells in contact with gastric fluid after oral administration and maintains a relative integrity of shape and a bulk density of less than one within the outer gelatinous barrier. The air trapped by the swollen polymer confers buoyancy to these dosage forms.
Hydrodymamically balance system (HBS) was first design by Sheth and Tossounian in 1975. Such systems contains drug with gel forming hydrocolloids meant to remain buoyant on stomach contents. This system incorporate a high level of one or more gel forming highly swellable cellulose type hydrocolloids e.g. HEC, HPMC, NaCMC, Polysacchacarides and matrix forming polymers such as polycarbophil, polyacrylates and polystyrene, incorporated either in tablets or in capsules. On coming in contact with gastric fluid, the hydrocolloid in the system hydrates and forms a colloidal gel barrier around the gel surface. The air trapped by the swollen polymer maintains a density less than unity and confers buoyancy to this dosage forms19.
This technology is based on the encapsulation of drug reservoir inside a microporous compartment with aperture along its top and bottom wall. The peripheral walls of the drug reservoir compartment are completely sealed to prevent any direct contact of the gastric mucosal surface with the undissolved drug. In stomach the floatation chamber containing entrapped air causes the delivery system to float over the gastric contents. Gastric fluid enters through the apertures, dissolves the drug, and carries the dissolve drug for continuous transport across the intestine for absorption.
Multiple unit floating dosage forms have been developed from freeze-dried calcium alginate. Spherical beads of approximately 2.5 mm in diameter can be prepared by dropping a sodium alginate solution in to aqueous solutions of calcium chloride, causing precipitation of calcium alginate. The beads are then separated snap and frozen in liquid nitrogen, and freeze dried at -40° for 24 h, leading to the formation of porous system, which can maintain a floating fource over 12 h.
Hollow microspheres (microballons), loaded with ibuprofen in their outer polymer
shells were prepared by a novel emulsion-solvent diffusion method. The ehanol: dichloromethane solution of the drug and an enteric acrylic polymer was poured in to an agitated aqueous solution of PVA that was thermally controlled at 40°.The gas phase generated in dispersed polymer droplet by evaporation of dichloromethane formed in internal cavity in microspheres of the polymer with drug. The microballons floated continuously over the surface of acidic dissolution media containing surfactant for greater than 12 h in vitro.
1.Improves patient compliance by decreasing dosing frequency.
2.Bioavailability enhances despite first pass effect because fluctuations in plasma drug concentration is avoided, a desirable plasma drug concentration is maintained by continuous drug release.
3.Gastric retention time is increased because of buoyancy.
4.Enhanced absorption of drugs which solubilise only in stomach
5.Drug releases in controlled manner for prolonged period.
6.Site-specific drug delivery to stomach can be achieved.
7.Superior to single unit floating dosage forms as such microspheres releases drug uniformly and there is no risk of dose dumping.
8.Avoidance of gastric irritation, because of sustained release effect.
9.Better therapeutic effect of short half-life drugs can be achieved.
Floating microspheres are gastro-retentive drug delivery systems based on non-effervescent approach. Hollow microspheres are in strict sense, spherical empty particles without core. These microspheres are characteristically free flowing powders consisting of proteins or synthetic polymers, ideally having a size less than 200 micrometer. Solid biodegradable microspheres incorporating a drug dispersed or dissolved throughout particle matrix have the potential for controlled release of drugs20. Gastro-retentive floating microspheres are low-density systems that have sufficient buoyancy to float over gastric contents and remain in stomach for prolonged period. As the system floats over gastric contents, the drug is released slowly at desired rate resulting in increased gastric retention with reduced fluctuations in plasma drug concentration.
When microspheres come in contact with gastric fluid the gel formers, polysaccharides, and polymers hydrate to form a colloidal gel barrier that controls the rate of fluid penetration into the device and consequent drug release. As the exterior surface of the dosage form dissolves, the gel layer is maintained by the hydration of the adjacent hydrocolloid layer. The air trapped by the swollen polymer lowers the density and confers buoyancy to the microspheres. However a minimal gastric content needed to allow proper achievement of buoyancy21, 22. Hollow microspheres of acrylic resins, eudragit, polyethylene oxide, and cellulose acetate; polystyrene floatable shells; polycarbonate floating balloons and gelucire floating granules are the recent developments.
Hollow microspheres are prepared by solvent diffusion and evaporation methods to create the hollow inner core. Polymer is dissolved in an organic solvent and the drug is either dissolved or dispersed in the polymer solution. The solution containing the drug is then emulsified into an aqueous phase containing polyvinyl alcohol to form oil in water emulsion. After the formation of a stable emulsion, the organic solvent is evaporated either by increasing the temperature under pressure or by continuous stirring. The solvent removal leads to polymer precipitation at the o/w interface of droplets, forming cavity and thus making them hollow to impart the floating properties23,24.
Cellulose acetate, Chitosan, Eudragit, Acrycoat, Methocil, Polyacrylates, Polyvinyl acetate, Carbopol, Agar, Polyethylene oxide, Polycarbonates, Acrylic resins and Polyethylene oxide.
Floating microspheres are characterized by their micromeritic properties such as particle size, tapped density, compressibility index, true density and flow properties25. Particle size is measured using an optical microscopy and mean particle size was calculated by measuring 200 to 300 particles with the help of calibrated ocular micrometer. True density is determined by liquid displacement method; tapped density and compressibility index are calculated by measuring the change in volume using a bulk density apparatus; angle of repose is determined by fixed funnel method. The hollow nature of microspheres is confirmed by scanning electron microscopy26-28.
The compressibility index was calculated using following formula:
I = Vb –Vt / Vb x 100
Where, Vb is the bulk volume and Vt is the tapped volume. The value given below 15% indicates a powder with usually give rise to good flow characteristics, whereas above 25% indicate poor flow ability.
Fifty milligrams of the floating microspheres were placed in 100 ml of the simulated gastric fluid (SGF, pH 2.0) containing 0.02% w/v Tween 20. The mixture was stirred at 100 rpm with a magnetic stirrer. After 8 hours, the layer of buoyant microspheres was pipetted and separated by filtration. Particles in the sinking particulate layer were separated by filtration. Particles of both types were dried in a desiccator until constant weight was achieved. Both the fractions of microspheres were weighed and buoyancy was determined by the weight ratio of floating particles to the sum of floating and sinking particles29.
Buoyancy (%) = Wf / Wf + Ws
Where, Wf and Ws are the weights of the floating and settled microparticles
The release rate of floating microspheres was determined in a United States Pharmacopoeia (USP) XXIII basket type dissolution apparatus. A weighed amount of floating microspheres equivalent to 50 mg drug was filled into a hard gelatin capsule (No. 0) and placed in the basket of dissolution rate apparatus. Five hundred milliliters of the SGF containing 0.02% w/v of Tween 20 was used as the dissolution medium. The dissolution fluid was maintained at 37 ± 1° at a rotation speed of 100 rpm. Perfect sink conditions prevailed during the drug release study. 5ml samples were withdrawn at each 30 min interval, passed through a 0.25 μm membrane filter (Millipore), and analyzed using LC/MS/MS method to determine the concentration present in the dissolution medium. The initial volume of the dissolution fluid was maintained by adding 5 ml of fresh dissolution fluid after each withdrawal. All experiments were run in triplicate.
The in-vivo floating behavior can be investigated by X-ray photography of hollow microspheres loaded with barium sulphate in the stomach of beagle dogs. The in-vitro drug release studies are performed in a dissolution test apparatus using 0.1N hydrochloric acid as dissolution media. The in-vivo plasma profile can be obtained by performing the study in suitable animal models (e.g. beagle dogs).
1. The floating microspheres can be used as carriers for drugs with so-called absorption windows, these substances, for example antiviral, antifungal and antibiotic agents (Sulphonamides, Quinolones, Penicillins, Cephalosporins, Aminoglycosides and Tetracyclines) are taken up only from very specific sites of the GI mucosa.
2. Hollow microspheres of non-steroidal anti inflammatory drugs are very effective for controlled release as well as it reduces the major side effect of gastric irritation; for example floating microspheres of Indomethacin are quiet beneficial for rheumatic patients.
3. Floating microspheres are especially effective in delivery of sparingly soluble and insoluble drugs. It is known that as the solubility of a drug decreases, the time available for drug dissolution becomes less adequate and thus the transit time becomes a significant factor affecting drug absorption. For weakly basic drugs that are poorly soluble at an alkaline pH, hollow microspheres may avoid chance for solubility to become the rate-limiting step in release by restricting such drugs to the stomach. The positioned gastric release is useful for drugs efficiently absorbed through stomach such as Verapamil hydrochloride. The gastro-retentive floating microspheres will alter beneficially the absorption profile of the active agent, thus enhancing its bioavailability.
4. Hollow microspheres can greatly improve the pharmacotherapy of the stomach through local drug release, leading to high drug concentrations at the gastric mucosa, thus eradicating Helicobacter pylori from the sub-mucosal tissue of the stomach and making it possible to treat stomach and duodenal ulcers, gastritis and oesophagitis.31
5. The drugs recently reported to be entrapped in hollow microspheres include Prednisolone, Lansoprazole, Celecoxib, Piroxicam, Theophylline, Diltiazem hydrochloride, Verapamil hydrochloride and Riboflavin, Aspirin, Griseofulvin,Ibuprofen, Terfenadine.
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Punam Gaba, Monika Gaba, Rajeev Garg and Dr. G. D. Gupta
Ms. Punam Gaba is working a lecturer cum research scholar in department of pharmaceutics in ASBASJSM College of Pharmacy, Bela, Ropar, India. She had completed her graduation and post graduation from ASBASJSM College of Pharmacy, Bela, Ropar, India. She has very good academic and extra circular record.
Department of Pharmaceutics, ASBASJSM College of Pharmacy, Bela, Ropar, India
firstname.lastname@example.org; Ph No. 9872364239
Ms. Monika Gaba is working a lecturer cum research scholar in department of pharmaceutical chemistry in ASBASJSM College of Pharmacy, Bela, Ropar , India . She had completed her post graduation from Punjabi University , Patiala , India . She has very good academic and extra circular record. Email: email@example.com: Ph No. 9872390321
Mr. Rajeev Garg is working a lecturer cum research scholar in department of pharmaceutics in ASBASJSM College of Pharmacy, Bela, Ropar , India . He had completed his graduation from Rameesh institutions, Greater Noida and post graduation from B.N.College of pharmacy, Udaipur , Raj. He has very good academic and extra circular record.
Dr.G.D.Gupta is working as a professor and principal in ASBASJSM College of Pharmacy, Bela, Ropar , India . Dr. Gupta has author of number of books and published more than 100 Research Paper / Abstract in National and International conferences.